As described in an earlier application, WO2012/120399, the spiro-azetidine isobenzofuran derivatives were prepared using a substituent, i.e., protecting group, to block or protect the amine moiety on the compound. For example, non-limiting amine protecting groups include acyl groups, acyloxy groups, diphenylmethane, and benzylcarbamates. Removal of the BOC protecting group was accomplished under acidic conditions with subsequent coupling reactions to obtain the chiral amides. Further, the process for preparing the crystalline form of (S)-1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone is fully described in PCT/US2013/56945.
The present invention provides an improved process for preparing the methylsulfonylethanone spiro[azetidine-3,1-isobenzofuran]isoxazoline derivatives. The benzenesulfonic acid salt of the intermediate amine is neutralized and then undergoes simple coupling with a nitrophenyl sulfonylacetate reactant.